Effects of recombinant human macrophage colony-stimulating factor on plasma cholesterol levels

Recombinant human macrophage colony-stimulating factor (rhM-CSF) is a hematopoietic growth factor that stimulates the growth, differentiation, proliferation, and activation of cells of the monocyte/macrophage lineage. rhM-CSF was administered to rabbits and nonhuman primates to evaluate effects on cholesterol homeostasis. Decreases in plasma cholesterol concentrations were observed during rhM- CSF administration. The observed mean (+/- SD) decreases over a range of doses in nonhuman primates receiving rhM-CSF by continuous intravenous infusion (CIVI) or intravenous bolus (IVB) injection were approximately 16% +/- 8% and 43% +/- 10%, respectively. Low-density lipoprotein (LDL) cholesterol levels decreased 55% +/- 9% from pretreatment baseline values in the animals receiving rhM-CSF by IVB. Normocholesterolemic New Zealand white rabbits receiving rhM-CSF over a range of doses by CIVI showed a decrease from baseline in total cholesterol of approximately 28% +/- 17%, with LDL cholesterol levels decreasing by approximately 72% +/- 33%, while high-density lipoprotein levels showed variable changes, including increased values. A decrease of 36% +/- 26% in total plasma cholesterol was observed in Watanabe Heritable Hyperlipidemic rabbits receiving rhM-CSF by CIVI for 7 days. This decrease was attributable almost entirely to decreases in LDL cholesterol, which fell approximately 34% +/- 24% from baseline. Although the mechanism of this cholesterol-lowering effect is unknown, these results strongly suggest that rhM-CSF may provide a novel treatment for hypercholesterolemia and may be useful in investigations into the mechanisms of cholesterol homeostasis and atherogenesis.

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Effects of recombinant human macrophage colony-stimulating factor on plasma cholesterol levels

Blood ◽

10.1182/blood.v77.4.750.750 ◽

1991 ◽

Vol 77 (4) ◽

pp. 750-755 ◽

Cited By ~ 32

Author(s):

JB Stoudemire ◽

MB Garnick

Keyword(s):

Nonhuman Primates ◽

Ldl Cholesterol ◽

Plasma Cholesterol ◽

Density Lipoprotein ◽

Cholesterol Homeostasis ◽

Human Macrophage ◽

Cholesterol Levels ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Abstract Recombinant human macrophage colony-stimulating factor (rhM-CSF) is a hematopoietic growth factor that stimulates the growth, differentiation, proliferation, and activation of cells of the monocyte/macrophage lineage. rhM-CSF was administered to rabbits and nonhuman primates to evaluate effects on cholesterol homeostasis. Decreases in plasma cholesterol concentrations were observed during rhM- CSF administration. The observed mean (+/- SD) decreases over a range of doses in nonhuman primates receiving rhM-CSF by continuous intravenous infusion (CIVI) or intravenous bolus (IVB) injection were approximately 16% +/- 8% and 43% +/- 10%, respectively. Low-density lipoprotein (LDL) cholesterol levels decreased 55% +/- 9% from pretreatment baseline values in the animals receiving rhM-CSF by IVB. Normocholesterolemic New Zealand white rabbits receiving rhM-CSF over a range of doses by CIVI showed a decrease from baseline in total cholesterol of approximately 28% +/- 17%, with LDL cholesterol levels decreasing by approximately 72% +/- 33%, while high-density lipoprotein levels showed variable changes, including increased values. A decrease of 36% +/- 26% in total plasma cholesterol was observed in Watanabe Heritable Hyperlipidemic rabbits receiving rhM-CSF by CIVI for 7 days. This decrease was attributable almost entirely to decreases in LDL cholesterol, which fell approximately 34% +/- 24% from baseline. Although the mechanism of this cholesterol-lowering effect is unknown, these results strongly suggest that rhM-CSF may provide a novel treatment for hypercholesterolemia and may be useful in investigations into the mechanisms of cholesterol homeostasis and atherogenesis.

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Human Granulocyte-Macrophage Colony-Stimulating Factor Lowers the Levels of Plasma Cholesterol with an Increase in mRNA for Very Low Density Lipoprotein Receptor in Rabbitsa

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1994.tb17377.x ◽

2006 ◽

Vol 748 (1) ◽

pp. 630-633 ◽

Cited By ~ 4

Author(s):

T. ISHIBASHI ◽

K. YOKOYAMA ◽

J. SHINDO ◽

Y. HAMAZAKI ◽

Y. ENDO ◽

...

Keyword(s):

Plasma Cholesterol ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Very Low Density Lipoprotein ◽

Lipoprotein Receptor ◽

Colony Stimulating Factor ◽

Density Lipoprotein Receptor ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

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Effects of parenteral recombinant human macrophage colony-stimulating factor on monocyte number, phenotype, and antitumor cytotoxicity in nonhuman primates

Blood ◽

10.1182/blood.v75.10.2042.bloodjournal75102042 ◽

1990 ◽

Vol 75 (10) ◽

pp. 2042-2048 ◽

Cited By ~ 1

Author(s):

DH Munn ◽

MB Garnick ◽

NK Cheung

Keyword(s):

Nonhuman Primates ◽

Clinical Symptoms ◽

Progressive Increase ◽

Human Macrophage ◽

Colony Stimulating Factor ◽

Hla Dr ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Recombinant human macrophage colony-stimulating factor (rhM-CSF) was given to cynomolgus monkeys by continuous intravenous infusion or subcutaneous injection, at a dose of 50 to 100 micrograms/kg/d in repetitive 14-day cycles. Starting within 24 to 48 hours of initiation of rhM-CSF, there was a progressive increase in the number of circulating monocytes, from a baseline of 811 +/- 253 cells/microL to a peak of 3,495 +/- 712 cells/microL on day 5 to 7. Many of these cells were large, granular, and extensively vacuolated. The expanded cell population expressed HLA-DR, LFA3, CD11b (904), and CD14 (MY4), and was 77% CD16 (FcRIII) positive by two-color cytofluorometry. In functional assays, fresh monocytes showed little cytotoxicity against cultured human melanoma cells (SKMel-1), with or without prior rhM-CSF treatment. However, after 3 days of in vitro culture in rhM-CSF, monocytes from treated animals mediated efficient antibody-dependent cytotoxicity (ADCC) against SKMel-1 using the murine monoclonal antibody 3F8 (IgG3, anti-ganglioside GD2). Under the same conditions, monocytes from control animals showed little ADCC (17% versus 82%, P less than .05). Antitumor cytotoxicity in the absence of antibody was less efficient and was not significantly different between the two groups. There was a mild decrease in platelet count during rhM-CSF treatment, without clinical symptoms. No abnormalities of serum biochemical parameters were seen. We conclude that parenteral rhM-CSF increases the number of circulating monocytes in nonhuman primates, and that these monocytes mediate increased antitumor ADCC after a brief period of in vitro differentiation. This study has implications for the design of possible future clinical trials combining antitumor monoclonal antibodies and rhM-CSF.

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Recombinant human macrophage colony-stimulating factor reduces plasma cholesterol and carrageenan granuloma foam cell formation in Watanabe heritable hyperlipidemic rabbits.

Arteriosclerosis and Thrombosis A Journal of Vascular Biology ◽

10.1161/01.atv.14.1.70 ◽

1994 ◽

Vol 14 (1) ◽

pp. 70-76 ◽

Cited By ~ 15

Author(s):

R G Schaub ◽

M P Bree ◽

L L Hayes ◽

M A Rudd ◽

L Rabbani ◽

...

Keyword(s):

Foam Cell ◽

Plasma Cholesterol ◽

Cell Formation ◽

Foam Cell Formation ◽

Human Macrophage ◽

Colony Stimulating Factor ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

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Effects of parenteral recombinant human macrophage colony-stimulating factor on monocyte number, phenotype, and antitumor cytotoxicity in nonhuman primates

Blood ◽

10.1182/blood.v75.10.2042.2042 ◽

1990 ◽

Vol 75 (10) ◽

pp. 2042-2048 ◽

Cited By ~ 43

Author(s):

DH Munn ◽

MB Garnick ◽

NK Cheung

Keyword(s):

Nonhuman Primates ◽

Clinical Symptoms ◽

Progressive Increase ◽

Human Macrophage ◽

Colony Stimulating Factor ◽

Hla Dr ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Abstract Recombinant human macrophage colony-stimulating factor (rhM-CSF) was given to cynomolgus monkeys by continuous intravenous infusion or subcutaneous injection, at a dose of 50 to 100 micrograms/kg/d in repetitive 14-day cycles. Starting within 24 to 48 hours of initiation of rhM-CSF, there was a progressive increase in the number of circulating monocytes, from a baseline of 811 +/- 253 cells/microL to a peak of 3,495 +/- 712 cells/microL on day 5 to 7. Many of these cells were large, granular, and extensively vacuolated. The expanded cell population expressed HLA-DR, LFA3, CD11b (904), and CD14 (MY4), and was 77% CD16 (FcRIII) positive by two-color cytofluorometry. In functional assays, fresh monocytes showed little cytotoxicity against cultured human melanoma cells (SKMel-1), with or without prior rhM-CSF treatment. However, after 3 days of in vitro culture in rhM-CSF, monocytes from treated animals mediated efficient antibody-dependent cytotoxicity (ADCC) against SKMel-1 using the murine monoclonal antibody 3F8 (IgG3, anti-ganglioside GD2). Under the same conditions, monocytes from control animals showed little ADCC (17% versus 82%, P less than .05). Antitumor cytotoxicity in the absence of antibody was less efficient and was not significantly different between the two groups. There was a mild decrease in platelet count during rhM-CSF treatment, without clinical symptoms. No abnormalities of serum biochemical parameters were seen. We conclude that parenteral rhM-CSF increases the number of circulating monocytes in nonhuman primates, and that these monocytes mediate increased antitumor ADCC after a brief period of in vitro differentiation. This study has implications for the design of possible future clinical trials combining antitumor monoclonal antibodies and rhM-CSF.

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